17.5% of Lung Cancer Patients Never Smoked; Genetics & Toxins to Blame

17.5% of Lung Cancer Patients are Non-Smokers

It started with a sharp pain in her right side whenever she coughed or sneezed. At first, Stephanie Dunn Haney thought she’d broken a rib, so she decided to wait and see if the pain went away by itself. A year and a half later it was still there, so she went to her doctor, who performed an X-ray and found nothing. During the next 18 months, she had MRI scans, ultrasound, physiotherapy and chiropractic therapy. Still the pain didn’t go away.

17.5% of Lung Cancer Patients are Non-SmokersDunn Haney began to suspect something more serious, but her doctor reassured her.

“She told me that she couldn’t promise it wasn’t something like cancer, but there was nothing to indicate that’s what it would be,” Dunn Haney recalls.

She had never smoked and had no family history of cancer, but Dunn Haney eventually persuaded her doctor to do a CAT scan. It revealed a shadow on her lung — probably an old infection. She was referred to a specialist to double-check. He too said it was unlikely to be cancer, but Dunn Haney insisted on undergoing surgery to remove a sliver of lung tissue for testing.

In October 2007, 3-1/2 years after her symptoms first appeared, she was diagnosed with stage IV lung cancer — as advanced as it can get.

Worldwide, more people die of lung cancer than from any other form, and the main risk factor is smoking. But lung cancer in people who’ve never smoked seems to be on the rise. In the U.S., 17.5 percent of lung cancers occur in this group, and among women the figure is even higher. In Southeast Asia more than 50 percent of women who get lung cancer have never smoked.

In fact, if this kind of lung cancer was regarded as a separate disease, it would rank as the seventh most common cause of death from cancer worldwide — the sixth in the U.S.

“You’re talking about three or four times as many people who have never smoked dying from lung cancer as die from cervical cancer,” says Mick Peake, a respiratory physician at the University of Leicester, UK.

New research suggests lung cancer in those who’ve never smoked is indeed a very different disease. And if lung cancer patients were promptly referred for genetic testing and tailored treatment, rather than all being lumped together, they could have better survival prospects. Meanwhile, a study presented at a meeting of the American Society of Clinical Oncology in Chicago in June shows that such prompt referral is feasible, even for those without access to specialist cancer centers.

People who’ve never smoked may be genetically predisposed to lung cancer or may get it from exposure to air pollution. Sometimes second-hand smoke is to blame — even as the number of people who smoke is diminishing in many countries as a result of public health campaigns.

Yet these health warnings seem to have had an unintended effect. Although they have dramatically cut smoking rates, they may also have stigmatized lung cancer patients and left both the public and some medical practitioners believing the disease is inevitably fatal. Recent research suggests that these factors mean people with lung cancer are less likely to be referred to an oncologist than those with other cancers.

In a 2007 study of 672 family doctors in the U.S, 34 percent said they would refer a patient with advanced breast cancer and a poor prognosis to a cancer specialist. Just 20 percent said they would take this action with a lung cancer patient in similar health (Journal of Thoracic Oncology).

“The nihilism associated with lung cancer is a big problem,” says Joan Schiller of the University of Texas Southwestern Medical Center in Dallas, who supervised the study.

A new study of 36 lung cancer patients in Wisconsin raised similar concerns.

“A key issue is a lack of symptom recognition among primary physicians, particularly for patients without a smoking history,” says Regina Vidaver, executive director of the National Lung Cancer Partnership, Madison, Wis., who’s leading the work. “There’s a lot of delay in getting the patients to diagnosis.” In one case, she says, a lung specialist refused to refer a patient to an oncologist because he believed nothing could be done. “He was simply told to go home and get his affairs in order.”

Many suspect this negative attitude may explain why lung cancer gets a fraction of the funding allotted to other cancers. In the UK, lung cancer received just 5 percent of the funding targeted at specific types of cancer in 2010, while 19 percent went to breast cancer. If you compare how much gets spent against the death rates for various cancers, the picture is even more startling. In the U.S., every death from breast cancer receives $26,398 of research funding, compared with just $1,442 per lung cancer death.

And yet what research is being done into lung cancer paints an unexpected picture of the disease — one in which lung cancer in those who’ve never smoked is emerging as a separate illness with its own outlook.

Good Mutations

Several years ago, Dr. Paul Paik at Memorial Sloan-Kettering Cancer Center in New York City and his colleagues discovered that people who’ve never smoked survived about twice as long with lung cancer as current or former smokers. Since then, they’ve been trying to figure out why.

In May, they published an analysis of tumors from 293 never-smokers and 382 current or former smokers. The study revealed significant differences in three genes that encode key cell-signaling proteins. Mutations in these genes can drive cancer growth.

The never-smokers were more than twice as likely as current or former smokers to possess mutations in the EGFR gene and six times as likely to carry a mutation in ALK. Meanwhile, 10 times as many current or former smokers as non-smokers carried a mutated form of a third gene, KRAS (Cancer).

“Never-smokers seem to have more good-prognosis mutations. Survival for patients with KRAS mutations is much worse,” says Paik.

Some of Paik’s colleagues have also been studying lung cancer patients who only smoked for a few years, typically while at college. The mutations driving their cancers seem to fall somewhere in between those of smokers and never-smokers.

The good news is that we can test for many of these genetic mutations, and even target them with drugs. Leading this wave are erlotinib (sold as Tarceva), which targets EGFR mutations, and crizotinib (sold as Xalkori), which does the same for ALK mutations. Drugs targeting KRAS mutations are also in clinical trials.

Targeted drugs seem to be particularly effective in never-smokers, whose tumors tend to have just one or two mutations. Tumors in smokers can contain hundreds of different mutations and are therefore harder to treat.

“While we’re not talking about a cure, a lot of people who have the EGFR or ALK mutation do spectacularly well on these targeted drugs,” says Peake. “The cancers usually do come back, but you can add 18 months or more on a life.”

The challenge now is to change healthcare workers’ perception of lung cancer to ensure that people get prompt and tailored treatment, rather than being dismissed as a lost cause.

“The main barriers are the availability and awareness of molecular testing,” says Thomas Zander, of University Hospital, Cologne, Germany.

At the Chicago meeting in June, Zander explained how, with colleagues in Cologne, he founded a genomic medicine lung cancer network. The network provides a molecular testing service to non-specialist hospitals in the area. In its first 18 months, it handled 2,000 samples from nearby hospitals. In almost 80 percent of cases a molecular diagnosis was possible.

Until networks like Zander’s are more common, many patients face an uphill battle to get the right diagnosis and access to potentially effective drugs.

The first oncologist Dunn Haney saw offered her standard chemotherapy and told her molecular testing was pointless at that stage.

“I said that you need to understand, I’m 39 years old and I have a 2-1/2-year-old and a 4-1/2-year-old at home. I have got to beat this,” she says. “I was told that’s very good, working with fighters is good. The only challenge is sometimes they don’t know when to stop fighting.”

She sought a second, and then a third opinion. Finally, she found a doctor in Pennsylvania who pointed out that while advanced lung cancer generally isn’t curable, it can be managed just like diabetes or heart disease. After chemotherapy, Dunn Haney was put onto Tarceva and Avastin, drugs that kept her cancer in check for two years. When it started to grow back, her cancer tested positive for the ALK mutation so she switched to Xalkori.

It’s now eight years since her symptoms began.

“I have fairly normal energy levels and no one really knows I’m sick,” she says. Her doctor also has a back-up plan if Xalkori fails: an experimental drug called LDK 378, which targets the ALK mutation in a slightly different way.

Her daughters, Libby and Allie, are now 9 and 7, and for every childhood milestone that passes, Dunn Haney feels grateful.

“Whether it’s teeth or sports wins or finishing a grade, it’s not so important that I see them as it is that they know their mother was there to see them,” she says.

–  Linda Geddes, New Scientist Magazine


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